Principles of Drug Action: Drug Metabolism I

Principles of Drug Action: Chemical Basis of Drug Metabolism I

• Lecture 24 covers the chemical basis of drug metabolism.
• Medicinal chemistry focuses on drug-target interactions, drug discovery, development, and optimization.
• Physicochemical properties of drugs include functional groups (FG), acidity/basicity, salt and solubility, and chirality.
• Drug targets include enzymes and receptors.
• Drug metabolism is crucial for terminating drug activity, determining the duration and intensity of the pharmacological response, and converting prodrugs to active drugs.
• Drug metabolism primarily occurs in the liver, but also in other organs (GI, kidney, lung, skin, CNS, placenta, fetus).
• Microsomes, cytosol, and mitochondria are involved in drug metabolism.
• The first-pass effect describes the metabolism of orally absorbed drugs in the liver before systemic distribution.

Drug Metabolism Phases

• Drug metabolism occurs in two main phases: Phase I and Phase II.
• Phase I reactions (oxidation, reduction, hydrolysis) add polar handles to the molecule (e.g. OH, -NH2, -COOH).
• Cytochrome P450 (CYP450) enzymes are crucial for Phase I oxidation reactions.
• Phase II reactions involve conjugation (adding endogenous compounds) to the drug molecules.
• Phase I reactions often prepare molecules for Phase II reactions.

Pharmacokinetics: ADME

• Pharmacokinetics describes how the body handles drugs.
• Absorption, Distribution, Metabolism, and Excretion (ADME) are key concepts of pharmacokinetics.
• Absorption (how drugs enter the body) and Distribution (where drugs go in the body) are key processes.
• Metabolism (how drugs are broken down) and Excretion (how drugs leave the body) are essential processes following distribution.
• The liver plays a key role in drug metabolism.

Drug Distribution

• Drug distribution happens rapidly from blood vessels to tissues and organs through leaky blood vessels.
• Drugs cross blood vessel walls quickly through gaps between cells.
• Drug distribution fills the entire blood supply within 1 minute of absorption..
• Uneven distribution around the body based on blood supply.
• Distribution, binding to macromolecules, storage in fat tissue (e.g. barbiturates) or bone cause Blood concentration to drop rapidly after absorption..

CYP450

• CYP450 enzymes catalyze oxidation and reduction reactions.
• CYP450 contains a heme molecule bound to an iron atom.
• CYP450's role in drug metabolism involves inserting oxygen atoms into drug molecules and is key to the process.
• Different CYP450 isoforms exist, influencing patient variability in drug metabolism and potential side-effects.
• The mechanism of CYP450 enzymatic oxidation involves the addition of oxygen molecules and the addition of hydrogens based on the steps (reduction).

Drug-Drug & Drug-Food Interactions

• Drugs impacting CYP450 activity can affect the metabolism of other drugs, resulting in variations in needed dosages.
• Foods like grapefruit juice may inhibit CYP450 activity, altering drug metabolism and dosages..
• Certain food and drug interactions exist.

Metabolic Pathways: Phase I Reactions

• Phase I metabolism converts chemicals to more polar metabolites by introducing or unmasking polar functional groups.
• This phase includes oxidation, reduction, and hydrolysis.
• Oxidation reactions add oxygen to or remove hydrogen from molecules, increasing their polarity. Reduction reactions add hydrogen atoms.. Hydrolysis reactions break bonds and add water molecules to metabolites.

Metabolic Pathways: Phase II Reactions

• Phase II reactions involve conjugation.
• Endogenous compounds bind to metabolites to further increase their polarity.
• This phase makes the metabolites more readily excreted from the body.

Drug Metabolism: Oxidation of Specific Functional Groups

• Aromatic rings, alkenes, aliphatic/ alicyclic carbon atoms, benzylic/ allylic carbon atoms, imine/carbonyl bonds, and amine, amide, and aromatic nitrogen atoms can undergo oxidation reactions by CYP450 enzymes..

Drug Metabolism: Reduction Reactions

• Reduction reactions involve adding hydrogen to or removing oxygen from metabolized substances by enzymes acting as biocatalysts.

Drug Metabolism: Hydrolysis

• Hydrolysis involves the addition of a water molecule to break a bond, typically occurs with esters, amides, and cyclic analogs.

Prodrugs

• Prodrugs are inactive compounds that are metabolized into active forms in the body.
• Prodrugs are often used to improve membrane permeability, lower the water solubility of foul-tasting drugs, mask toxicity/side effects, and enhance water solubility for intravenous administration.